The Splicing Factor FUBP1 Is Required for the Efficient Splicing of Oncogene MDM2 Pre-mRNA

Jacob, Aishwarya G.; Singh, Ravi; Mohammad, Fuad; Bebee, Thomas W.; Chandler, Dawn S.

doi:10.1074/jbc.m114.554717

Cited by 32 publications

(32 citation statements)

References 55 publications

(85 reference statements)

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“…hnRNP U, FUBP1, and ILF2 are not only transcription factors , but also alternative splicing regulators . Thus, we tested whether SRSF1, which is a well‐known alternative splicing regulator and is highly expressed in two‐ to eight‐cell stage mouse embryos (Fig C), is involved in the LincGET ‐protein complex.…”

Section: Resultsmentioning

confidence: 99%

A novel long intergenic noncoding RNA indispensable for the cleavage of mouse two‐cell embryos

Wang

et al. 2016

EMBO Reports

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Endogenous retroviruses (ERVs) are transcriptionally active in cleavage stage embryos, yet their functions are unknown. ERV sequences are present in the majority of long intergenic noncoding RNAs (lincRNAs) in mouse and humans, playing key roles in many cellular processes and diseases. Here, we identify LincGET as a nuclear lincRNA that is GLN-, MERVL-, and ERVK-associated and essential for mouse embryonic development beyond the two-cell stage. LincGET is expressed in late two- to four-cell mouse embryos. Its depletion leads to developmental arrest at the late G2 phase of the two-cell stage and to MAPK signaling pathway inhibition. LincGET forms an RNA-protein complex with hnRNP U, FUBP1, and ILF2, promoting the cis-regulatory activity of long terminal repeats (LTRs) in GLN, MERVL, and ERVK (GLKLTRs), and inhibiting RNA alternative splicing, partially by downregulating hnRNP U, FUBP1, and ILF2 protein levels. Hnrnpu or Ilf2 mRNA injection at the pronuclear stage also decreases the preimplantation developmental rate, and Fubp1 mRNA injection at the pronuclear stage causes a block at the two-cell stage. Thus, as the first functional ERV-associated lincRNA, LincGET provides clues for ERV functions in cleavage stage embryonic development.

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Section: Resultsmentioning

confidence: 99%

A novel long intergenic noncoding RNA indispensable for the cleavage of mouse two‐cell embryos

Wang

et al. 2016

EMBO Reports

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“…In addition to c-myc, p21, and USP29, two researches showed that the expression levels of stathmin mRNA were strongly correlated with that of FUBP1 mRNA in HCC and NSCLC [21, 25]. FUBP1 was also identified as a splicing regulator, which facilitated the efficient splicing of MDM2 pre-mRNA or induced exon exclusion [46, 47]. FUBP1 could directly and physically interact with p53 and suppress p53 transactivation activity under radiation treatment [29].…”

Section: Discussionmentioning

confidence: 99%

Upregulation of Far Upstream Element-Binding Protein 1 (FUBP1) Promotes Tumor Proliferation and Tumorigenesis of Clear Cell Renal Cell Carcinoma

Duan

Bao

et al. 2017

PLoS ONE

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ObjectiveThe far upstream element (FUSE)-binding protein 1 (FUBP1) is a transactivator of human c-myc proto-oncogene transcription, with important roles in carcinogenesis. However, the expression pattern and potential biological function of FUBP1 in clear cell renal cell carcinoma (ccRCC) is yet to be established.MethodsFUBP1 expression was detected in ccRCC tissues and cell lines by real-time RT-PCR, Western blot analysis, and immunohistochemistry. The correlations of FUBP1 mRNA expression levels with clinicopathological factors were evaluated. The biological function of FUBP1 during tumor cell proliferation was studied by MTS, colony formation, and soft-agar colony formation. The effects of FUBP1 on cell cycle distribution and apoptosis were analyzed by flow cytometry. Western blot analysis was used to identify the potential mechanism of FUBP1 regulating cell cycle and apoptosis.ResultsThe levels of FUBP1 mRNA and protein expression were upregulated in human ccRCC tissues compared with adjacent noncancerous tissues. High levels of FUBP1 mRNA expression were associated with higher tumor stage and tumor size. FUBP1 knockdown inhibited cell proliferation and induced cell cycle arrest and apoptosis. Meanwhile, the expression levels of c-myc and p21 mRNA were correlated with that of FUBP1 mRNA.ConclusionsFUBP1 acts as a potential oncogene in ccRCC and may be considered as a novel biomarker or an attractive treatment target of ccRCC.

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“…In addition, FBP family members affect messenger RNA (mRNA) abundance in a transcription‐independent manner. For example, FBP2 destabilizes interleukin‐8 mRNA, while FBP1 is involved in splicing of MDM2 …”

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confidence: 99%

“…For example, FBP2 destabilizes interleukin-8 mRNA, while FBP1 is involved in splicing of MDM2. (4,5) Overexpression of FBPs (and here especially FBP1) has been described for many malignancies such as hepatocellular carcinoma (HCC), (6,7) nonsmall-cell lung cancer, (8) and colorectal cancer. (9) Importantly, nuclear enrichment of FBPs correlated with poor overall survival of liver cancer patients.…”

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PI3K/AKT/mTOR‐dependent stabilization of oncogenic far‐upstream element binding proteins in hepatocellular carcinoma cells

et al. 2016

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Transcription factors of the far-upstream element-binding protein (FBP) family represent cellular pathway hubs, and their overexpression in liver cancer (hepatocellular carcinoma [HCC]) stimulates tumor cell proliferation and correlates with poor prognosis. Here we determine the mode of oncogenic FBP overexpression in HCC cells. Using perturbation approaches (kinase inhibitors, small interfering RNAs) and a novel system for rapalog-dependent activation of AKT isoforms, we demonstrate that activity of the phosphatidylinositol-4,5-biphosphate 3-kinase/AKT pathway is involved in the enrichment of nuclear FBP1 and FBP2 in liver cancer cells. In human HCC tissues, phospho-AKT significantly correlates with nuclear FBP1/2 accumulation and expression of the proliferation marker KI67. Mechanistic target of rapamycin (mTOR) inhibition or blockade of its downstream effector eukaryotic translation initiation factor 4E activity equally reduced FBP1/2 concentrations. The mTORC1 inhibitor rapamycin diminishes FBP enrichment in liver tumors after hydrodynamic gene delivery of AKT plasmids. In addition, the multikinase inhibitor sorafenib significantly reduces FBP levels in HCC cells and in multidrug resistance 2-deficient mice that develop HCC due to severe inflammation. Both FBP1/2 messenger RNAs are highly stable, with FBP2 being more stable than FBP1. Importantly, inhibition of phosphatidylinositol-4,5-biphosphate 3-kinase/AKT/mTOR signaling significantly diminishes FBP1/2 protein stability in a caspase-3/-7-dependent manner. Conclusion These data provide insight into a transcription-independent mechanism of FBP protein enrichment in liver cancer; further studies will have to show whether this previously unknown interaction between phosphatidylinositol-4,5-biphosphate 3-kinase/AKT/mTOR pathway activity and caspase-mediated FBP stabilization allows the establishment of interventional strategies in FBP-positive HCCs.

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The Splicing Factor FUBP1 Is Required for the Efficient Splicing of Oncogene MDM2 Pre-mRNA

Cited by 32 publications

References 55 publications

A novel long intergenic noncoding RNA indispensable for the cleavage of mouse two‐cell embryos

A novel long intergenic noncoding RNA indispensable for the cleavage of mouse two‐cell embryos

Upregulation of Far Upstream Element-Binding Protein 1 (FUBP1) Promotes Tumor Proliferation and Tumorigenesis of Clear Cell Renal Cell Carcinoma

PI3K/AKT/mTOR‐dependent stabilization of oncogenic far‐upstream element binding proteins in hepatocellular carcinoma cells

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